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TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel

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Anatomy. 0. 5. 10. 15. 0. 30. 60. 90. 180. 270. 360. 450 ... Male. STEMI. UA/NSTEMI. 0.5. 1. 2. Prasugrel Better. Clopidogrel Better. HR. Age. Reduction in risk ... – PowerPoint PPT presentation

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Title: TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel


1
TRial to Assess Improvement in Therapeutic
Outcomes by Optimizing Platelet InhibitioN with
Prasugrel
  • TRITON-TIMI 38AHA 2007Orlando, Florida

Disclosure Statement The TRITON-TIMI 38 trial
was supported by a research grant to the Brigham
and Womens Hospital from Daiichi Sankyo Co. Ltd
and Eli Lilly Co.
2
Antiplatelet Therapy for PCI
  • Dual antiplatelet Rx (ASA thienopyridine) is
    standard of care Ticlopidine
    Clopidogrel
  • Clinical need to improve on benefits observed
    with clopidogrel
  • Prasugrel Novel thienopyridine Efficient
    generation of active metabolite High levels of
    IPA achieved rapidly High IPA in clopidogrel
    hyporesponders Encouraging Phase 2 data

3
Study Goals
  • To test the hypothesis that higher and less
    variable IPA prevents clinical ischemic events.
  • To evaluate the safety of a regimen that produces
    higher IPA.
  • These goals were achieved by evaluating the
    efficacy and safety of prasugrel compared to
    clopidogrel in mod/high risk patients with ACS
    undergoing PCI on a background of ASA.

4
Study Design
ACS (STEMI or UA/NSTEMI) Planned PCI
N 13,600
ASA
Double-blind
CLOPIDOGREL 300 mg LD/ 75 mg MD
PRASUGREL 60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint CV death, MI, Stroke 2o
endpoints CV death, MI, Stroke, Rehosp-Rec
Isch CV death, MI, UTVR Stent Thrombosis
(ARC definite/prob.) Safety endpoints TIMI
major bleeds, Life-threatening bleedsKey
Substudies Pharmacokinetic, Genomic
5
Enrollment Criteria
  • Inclusion Criteria Planned PCI for
    Mod-High Risk UA/NSTEMI (TRS gt 3) STEMI lt
    14 days (ischemia or Rx strategy) STEMI
    Primary PCI
  • Major Exclusion Criteria
  • Severe comorbidity
  • Increased bleeding risk
  • Prior hemorrhagic stroke or any stroke lt 3 mos
  • Any thienopyridine within 5 days
  • No exclusion for advanced age or renal function

KnownAnatomy
6
Primary EndpointCV Death,MI,Stroke
15

Clopidogrel
12.1(781)
9.9 (643)
10
Primary Endpoint ()
Prasugrel
HR 0.81(0.73-0.90)P0.0004
HR 0.80P0.0003
HR 0.77P0.0001
5
NNT 46
LTFU 14 (0.1)
ITT 13,608
0
0
30
60
90
180
270
360
450
Days
7
Timing of Benefit(Landmark Analysis)
8

6.9
Clopidogrel
Clopidogrel
5.6
5.6
6
Primary Endpoint ()
4.7
4
Prasugrel
Prasugrel
HR 0.82P0.01
HR 0.80P0.003
2
1
0
0
1
2
3
0
30
60
90
180
270
360
450
Days
Loading Dose
Maintenance Dose
8
Stent Thrombosis(ARC Definite Probable)

3
Any Stent at Index PCI N 12,844
2.4(142)
Clopidogrel
2
Endpoint ()
1.1 (68)
1
Prasugrel
HR 0.48P lt0.0001
NNT 77
0
0
30
60
90
180
270
360
450
Days
9
Balance of Efficacy and Safety

15
138 events
Clopidogrel
HR 0.81(0.73-0.90)P0.0004
12.1
CV Death / MI / Stroke
9.9
10
NNT 46
Prasugrel
Endpoint ()
5
35 events
TIMI Major NonCABG Bleeds
Prasugrel
2.4
HR 1.32(1.03-1.68)P0.03
1.8
Clopidogrel
0
NNH 167
0
30
60
90
180
270
360
450
Days
10
Net Clinical BenefitDeath, MI, Stroke, Major
Bleed (non CABG)

15
13.9
Clopidogrel
ITT 13,608
12.2
HR 0.87P0.004
Prasugrel
10
Endpoint ()
All CauseMortality
5
Clop 3.2Pras 3.0 P0.64
0
0
30
60
90
180
270
360
450
Days
11
CV Death, MI, StrokeMajor Subgroups
Reduction in risk ()
18
UA/NSTEMI


B
21
STEMI
21
Male
12
Female
25
lt65
14
65-74
Age
6
gt75
14
No DM
30
DM
20
BMS
18
DES
21
GPI
16
No GPI
14
CrCl lt 60
20
CrCl gt 60
Pinter NS
19
OVERALL
0.5
1
2
Prasugrel Better
Clopidogrel Better
HR
12
Diabetic Subgroup
N3146

18
Clopidogrel
17.0
16
CV Death / MI / Stroke
14
12.2
12
HR 0.70Plt0.001
Endpoint ()
Prasugrel
10
NNT 21
8
6
TIMI Major NonCABG Bleeds
Clopidogrel
4
2.6
2.5
2
Prasugrel
0
0
30
60
90
180
270
360
450
Days
13
Net Clinical BenefitBleeding Risk Subgroups
Post-hoc analysis
Risk ()

54
Yes
Prior Stroke / TIA
-16
No
Pint 0.006
-1
gt75
Age
-16
Pint 0.18
lt 75
3
lt 60 kg
Wgt
Pint 0.36
-14
gt60 kg
-13
OVERALL
0.5
1
2
Prasugrel Better
Clopidogrel Better
HR
14
Bleeding Risk SubgroupsTherapeutic Considerations
Reduced MDGuided by PKAge gt 75 or Wt lt 60 kg
Avoid PrasugrelPrior CVA/TIA
16
4
Significant Net Clinical Benefit with
Prasugrel80
MD 10 mg
15
Comparison with Higher Dose Clopidogrel
IPA ( 20 mM ADP)
IPA ( 20 mM ADP)
Plt0.0001
Plt0.0001 for each
N201
Prasugrel 60 mg
Clopidogrel 600 mg
Prasugrel 10 mg
Clopidogrel 150 mg
Hours
14 Days
Wiviott et al Circ 2007 (In Press)
16
ConclusionsHigher IPA to Support PCI
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg
LD/ 75 mg MD
Net clinical benefit significantly favored
Prasugrel
Optimization of Prasugrel maintenance dosing in a
minority of patients may help improve the benefit
risk balance
17
Antiplatelet Therapy in ACS
ASA
ASA Clopidogrel
ASA Prasugrel
Reduction inIschemicEvents
- 22
- 20
- 19
Increase in Major Bleeds
32
38
60
Single Antiplatelet Rx
Dual Antiplatelet Rx
Higher IPA
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